Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and multiple internal organs. SSc-related pulmonary fibrosis is the most common cause of SSc-related mortality, but currently no adequate therapies exist. The insulin-like growth factor (IGF) system has been implicated in the pathogenesis of pulmonary fibrosis. The role of IGF-II in the pathogenesis of fibrosis has been unexplored. We demonstrate that IGF-II expression is increased in vivo and in vitro in SSc lung tissue and primary lung fibroblasts. We also demonstrate that SSc lungs have increased IGF-II expression in fibroblastic foci. Furthermore, "IGF-II mRNA and protein levels are increased in primary lung fibroblasts from explanted lungs of patients with SSc, and recombinant-IGF-ll stimulates collagen and fibronectin production in primary lung fibroblasts. Our hypothesis is that IGF-II is abnormally expressed in SSc-related pulmonary fibrosis and contributes to disease pathogenesis by increasing extracellular matrix (ECM) production in fibroblasts. We propose to confirm our findings using lung tissues and primary fibroblasts and quantify levels of IGF-II secreted by SSc lung fibroblasts compared to normal lung fibroblasts. Additionally, we will compare systemic IGF-II levels in SSc patients of the Pittsburgh Scleroderma Database and Serum Bank and a cohort of twins discordant for SSc, and correlate IGF-II levels with pulmonary fibrosis and other clinical variables. We will examine the mechanism by which recombinant IGF-II mediates its effects. Specifically, we will determine whether the pro-fibrotic effects of IGF-II are mediated via the IGF-IR and/or Insulin Receptor (IR)-A in SSc and normal lung fibroblasts. We will also identify the signaling cascade activated by IGF-II in the induction of a fibrotic phenotype. Our goals are to characterize the aberrant expression of IGF-II in SSc-related pulmonary fibrosis and examine the mechanism(s) by which IGF-II increases ECM production and induces fibrosis. Our studies will allow further insight into the role of IGF-II in SSc-related pulmonary fibrosis.